The metabolites urobilin and sphingomyelin (30:1) are associated with incident heart failure in the general population

Abstract

Aims We aimed to investigate whether metabolomic profiling of blood can lead to novel insights into heart failure pathogenesis or improved risk prediction. Methods and results Mass spectrometry‐based metabolomic profiling was performed in plasma or serum samples from three community‐based cohorts without heart failure at baseline (total n = 3924; 341 incident heart failure events; median follow‐up ranging from 4.6 to 13.9 years). Cox proportional hazard models were applied to assess the association of each of the 206 identified metabolites with incident heart failure in the discovery cohorts Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) (n = 920) and Uppsala Longitudinal Study of Adult Men (ULSAM) (n = 1121). Replication was undertaken in the independent cohort TwinGene (n = 1797). We also assessed whether metabolites could improve the prediction of heart failure beyond established risk factors (age, sex, body mass index, low‐density and high‐density lipoprotein cholesterol, triglycerides, lipid medication, diabetes, systolic and diastolic blood pressure, blood pressure medication, glomerular filtration rate, smoking status, and myocardial infarction prior to or during follow‐up). Higher circulating urobilin and lower sphingomyelin (30:1) were associated with incident heart failure in age‐adjusted and sex‐adjusted models in the discovery and replication sample. The hazard ratio for urobilin in the replication cohort was estimated to 1.29 per standard deviation unit, 95% confidence interval (CI 1.03–1.63), and for sphingomyelin (30:1) to 0.72 (95% CI 0.58–0.89). Results remained similar after further adjustment for established heart failure risk factors in meta‐analyses of all three cohorts. Urobilin concentrations were inversely associated with left ventricular ejection fraction at baseline in the PIVUS cohort (β = −0.70, 95% CI −1.03 to −0.38). No major improvement in risk prediction was observed when adding the top 2 metabolites (C‐index 0.787, 95% CI 0.752–0.823) or nine Lasso‐selected metabolites (0.790, 95% CI 0.754–0.826) to a modified Atherosclerosis Risk in Communities heart failure risk score model (0.780, 95% CI 0.745–0.816). Conclusions Our metabolomic profiling of three community‐based cohorts study identified associations of circulating levels of the haem breakdown product urobilin, and sphingomyelin (30:1), a cell membrane component involved in signal transduction and apoptosis, with incident heart failure.

Ergothioneine is associated with reduced mortality and decreased risk of cardiovascular disease

“…Acetylornithine was the only metabolite associated with a lower risk for stroke in the fully adjusted models, further studies are needed to investigate the potential mechanism linking high acetylornithine levels to better cardiometabolic health. Urobilin has to our knowledge not previously been associated with an increased risk of type 2 diabetes or mortality, but recently associated with an increased risk of heart failure 28. More research is needed to explain the association between haemoglobin breakdown components and CVD.…”

Urine Metabolites Associated with the Dietary Approaches to Stop Hypertension (DASH) Diet: Results from the DASH‐Sodium Trial

“…However, it is unclear if this metabolite can be considered a biomarker of sodium reduction, because water or fluid intake was not assessed in the DASH‐Sodium trial, and other factors such as liver dysfunction and gut microorganisms can influence levels of urobilin. [ 47,48 ]…”

Current Status of Metabolomic Biomarker Discovery: Impact of Study Design and Demographic Characteristics

“…One technical approach to improve trust in metabolomics is the introduction of replication studies [50][51][52]. Such studies are demonstrating demographical balance in both the discovery and validation cohorts and may account for different geographical regions.…”

“…Independent, replicable associations were discovered between the future risk of T2DM and three metabolites: N2,N2-dimethylguanosine, 7-methylguanine, and 3-hydroxytrimethyllysine [51]. Another Swedish study used plasma or serum samples from three community-based cohorts to identify metabolites associated with incident heart failure in a general population (total n = 3924; 341 incident heart failure events; median follow-up ranging from 4.6 to 13.9 years) and discovered associations between heart failure and circulating levels of urobilin and sphingomyelin (30:1) [52]. Elevated levels of sphingomyelin (30:1) linked to heart failure could not be explained by known associations between BMI and sphingomyelin (SM) in other studies (Table 1).…”